The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling.
Interleukin-1beta (IL-1beta), a proinflammatory cytokine, is elevated in cigarette smokers. To determine whether IL-1beta plays a role in the pathogenesis of cigarette smoke-induced emphysema and small airway remodeling, IL-1 receptor knockout (IL1RKO), TNF-alpha receptor knockout (TNFRKO), or C57Bl/6 (control) mice were exposed to cigarette smoke acutely or for up to 6 months. With a single acute exposure, smoke elevated IL-1beta in C57Bl/6 mice. IL1RKO mice were protected against acute smoke-mediated increases in lavage inflammatory cells and matrix breakdown. In C57Bl/6 mice, acute smoke-mediated increases in inflammatory cells, serum IL-1beta, and serum TNF-alpha were blocked by z-VAD-fmk, a pan-caspase inhibitor, or z-WEHD-fmk, a caspase-1 (IL-1-converting enzyme, [ICE]) inhibitor. With 6 months of exposure, IL-1beta was no longer increased, but IL-18 was elevated. After 6 months of exposure, IL1RKO mice were 65% protected against emphysema, whereas TNFRKO mice were 83% protected. Both strains were completely protected against small airway remodeling. Lavage desmosine, hydroxyproline, and hyaluronan, matrix breakdown markers, were elevated in C57 but not IL1RKO mice. We conclude that IL-1beta plays a significant role in induction of murine emphysema and small airway remodeling, and is comparable to TNF-alpha in its effects. The protective effects of caspase inhibitors appear to be related to inhibition of ICE and raise the question of whether models that ameliorate emphysema with caspase inhibitors are really blocking IL-1beta (and IL-18) activation rather than blocking apoptosis.
Churg
Andrew
A
Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T2B5, Canada. achurg@interchange.ubc.ca
Zhou
Steven
S
Wang
Xiaoshan
X
Wang
Rona
R
Wright
Joanne L
JL
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D003895:Desmosine / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D006820:Hyaluronic Acid / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D009929:Organ Size; D011656:Pulmonary Emphysema / Q000097:blood / Q000473:pathology*; D012907:Smoking / Q000009:adverse effects*
D015415:Biomarkers; D018836:Inflammation Mediators; D020382:Interleukin-18; D053583:Interleukin-1beta; D003895:Desmosine; D006820:Hyaluronic Acid